Project Summary Influenza B virus (IBV) causes seasonal epidemics in humans and is responsible for the major influenza disease burden in some years, although it receives less attention as compared with influenza A virus (IAV). Unlike IAVs that infect a wide range of species, IBV infections are almost exclusively restricted to humans, despite sporadic infections reported in seals. It is unclear whether other animal species can support the replication of IBV and serve as a reservoir. Recent studies led by Dr. Ma provide serological and experimental infection evidence that domestic pigs are susceptible to IBV infection. Swine herds previously exposed to porcine reproductive and respiratory syndrome virus (PRRSV) had a higher prevalence of IBV antibodies; the IBV genome was detected in nasal swabs collected from PRRSV seropositive pigs (Ran et al., JVI, 2015). It has been well documented that PRRSV causes host immunosuppression and its emergence in the latter part of the 1980s has changed the landscape of porcine infectious ecology and affected the overall health status of the global swine population. To date, little is known about the biology and evolution of IBVs in non-human species. The precise role of PRRSV infection on IBV replication and transmission in pigs is not completely understood. Based on Dr. Ma's published work, it is hypothesized that the introduction of PRRSV into the U.S. swine population has increased the permissiveness of swine to IBVs, thus creating a novel animal reservoir and a zoonotic source, for what has traditionally been considered a uniquely human pathogen. This hypothesis will be tested through two specific aims in this R21 proposal, one that will determine the impact of PRRSV on susceptibility of swine to human IBVs and one that will determine whether IBV replication in swine leads to genetic and antigenic divergence of swine and human IBVs. In specific aim 1, pig challenge experiments with IBV will be conducted as a function of persistent PRRSV infection. In specific aim 2, IBVs from naturally infected pigs will be isolated and compared with co-circulating seasonal human IBV strains in vitro and in vivo for viral replication and pathogenesis. The results of this study will provide novel insight into the biology and evolution of IBVs, especially as they relate to co-infection with PRRSV. Studying the differences between human and swine IBV isolates may improve understanding of how IBVs are maintained when they are not circulating in humans. The results of these experiments will likely reveal new information about the molecular mechanisms of IBV replication and evolution in non-human species, which is an important issue in the influenza research community.